1. Field of the Invention
The present invention is related to stilbenoid compounds as inhibitors for squamous carcinoma and hepatoma and the uses thereof. More specifically, the present invention is related to compounds capable of inhibiting the cell viability and proliferation of squamous cell carcinoma and hepatocellular carcinoma, the pharmaceutical compositions of said compounds, the method for treating cancer using said compounds, and the method of manufacture of said compounds.
2. The Prior Arts
Head and neck cancer is the sixth most common cancer worldwide and accounts for 6% of all cancer cases. However, it ranks the fourth most commonly occurred cancer in Taiwan. Head and neck cancer is a broad term of epithelial malignancies that occurred in the paranasal sinuses, nasal cavity, oral cavity, pharynx and larynx. Approximately 95% of histological type is squamous cell carcinoma (HNSCC), while others are salivary gland tumors, lymphomas and sarcomas. Nowadays, several risk factors related to HNSCC onset were identified. The most important risk factors in HNSCC are from tobacco and alcohol consumption. Other risk factors include inhalant industrial exposures, human papilloma virus (HPV) infection and Epstein-Barr virus (EBV) infection. Despite improvement in the therapy of HNSCC, patients still suffer from a very poor prognosis following progression after standard therapy regimens. Due to high recurrence and metastasis property, the survival rate of most of the patients is very low.
Currently, there are three main treatments for management of HNSCC, which are radiation therapy, surgery and chemotherapy. The primary treatments are radiation and surgery or both in combination of adjuvant treatment of chemotherapy. The optimal combination of treatments is dependent on the cancer sites and disease stages. Moreover, the most common drugs used in combination with radiation therapy, so called chemoradiation, are cisplatin (Market available brands: Platinol, Platinol-AQ), fluorouracil (Market available brands: Adrucil, Efudex, Fluoroplex) and cetuximab (Market available brand: Erbitux). Other chemotherapy drugs used include carboplatin (Market available brand: Paraplatin), docetaxel (Market available brand: Taxotere) and gemcitabine, paclitaxel (Market available brand: Taxol), methotrexate (Market available brands: Abitrexate, Folex, Folex PFS, Mexate, Mexate-AQ) and bleomycin (Market available brands Blenoxane).
In spite of their antitumor activities, a lot of side effects come with chemotherapy. The difficulties of side effects include high infection risk, bruising, anemia, nausea, vomiting, sore mouth, hearing loss, fatigue and hair loss, which bother HNSCC patients. Clinical observations have found that cisplatin can cause renal failure and cytotoxicity. Both cisplatin and taxanes can result in toxicities, including haematological toxicity, neurotoxicity, nephrotoxicity and ototoxicity. Fluorouracil, methotrexate and taxanes may induce mucosal cytoxicity that worsens the outcome after radiation therapy. So far, cisplatin-based chemotherapy is the most widely used treatment in HNSCC because of its superior survival benefits. However, there are limitations for the chemotherapy of cisplatin such as the high occurrence of drug resistance and the severe toxicity due to high dosage. An ideal HNSCC chemotherapy drug, which can be effective in antitumor activity while avoiding the recurrence and metastasis of HNSCC, should have low cytotoxicity and low side effects.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy in the world and the second most common cause for cancer-related death. It was more prevalent in Asia and Africa; however, it is now showing a rising incidence among Western countries. HCC, which is an aggressive tumor, frequently occurs in the setting of chronic liver diseases and cirrhosis. The major risk factors related to HCC include infections with hepatitis B virus (HBV) or hepatitis C virus (HCV), alcoholic liver diseases, and non-alcoholic fatty liver diseases. In western countries, type II diabetes and obesity are the two emerging causes of HCC. Clinically, HCC is often diagnosed late and shows extremely poor prognosis after standard therapy regimens as well as very low survival rate.
Currently, several treatment modalities are available for HCC, including surgical intervention (tumor resection and liver transplantation), percutaneous interventions (ethanol or acetic acid injection, radiofrequency thermal ablation, microwave ablation and cryoablation), transarterial interventions (embolization, chemoperfusion, or chemoembolization), systematic chemotherapy and molecularly target therapies. Drugs used in systemic chemotherapy can be categorized into cytotoxic drugs and molecular target drugs. Cytotoxic drugs includes Xeloda (capecitabine), Etoposide, Irinotecan, 5-Fu, Doxorubicin, Mitoxantrone, and Thymitaq (Nolatrexed), which exhibit powerful side effects and high occurrence of drug resistance. Molecular target drugs include Nexavar (sorafenib), Sutent (sunitinib), and Avastin (bevacizumab), etc, which also show high occurrence of drug resistance. Side effects by chemotherapy not only affect the quality of living of patients of HCC but also lower the survival rates.
The development of new drugs that are effective against HCC with low toxicity is one important task in the medical and pharmaceutical field. To conquer the side effects and reduce the morbidity and mortality of HCC at the same time, the development of novel systemic chemotherapy for advanced HCC treatment is of principal importance. The ideal chemotherapeutic drugs must possess antitumor properties with high efficacy and a very low cytotoxicity for patients.
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin. In 1939, Michio Takaoka first reported resveratrol isolated from the poisonous but medicinal Veratrum album, a variety of grandiflorum, in a Japanese article. Resveratrol is found in the skin of red grapes and in other fruits as well as in the roots of Japanese knotweed (Polygonum cuspidatum). The pharmacological effects of resveratrol include life extension, cardioprotective effects, antidiabetes, and anti-inflammatory effects. Besides, resveratrol shows anti-cancer effects in animal models. However, this pharmaceutical anti-cancer effect is restricted due to low bioavailability.
No marked toxicity of resveratrol were observed in the group of rat received 0.3 g/kg/day for 4 weeks. Previous studies had discussed the adverse effects of resveratrol which 104 patients (including placebo) had been tested. The highest doses were 5 g/70 kg for a single intake and 0.9 g/day for iterative administration. No serious adverse event was detected in any of these studies. Adverse events were mild and only lasted for a few days.
Pterostilbene is a natural phenolic stilbenoid which is a phytoalexin. Pterostilbene could be found in grapes, a variety of berries and medicinal plants. The pharmacological effects of pterostilbene are antimicrobial, antioxidant, anti-inflammatory, hypolipidemic, antidiabetic activities, and memory improvement. The side effects and toxicity of pterostilbene are very low. The results of 28 days subchronic toxicity study indicated that at dose up to 3.0 g/kg/day, no significant adverse biochemical parameters and toxic effects were noted.